Bovine leukemia virus (BLV) is an oncogenic retrovirus that causes lymphoid cancer in cattle with a long latency after infection. BLV and the human T cell leukemia viruses (HTLV) types I and II form a distinct group of oncogenic retroviruses whose mechanism of tumorigenesis is unknown. Their genomes are structually homologous; each contains a distantly related gene that encodes at least two nonvirion proteins. Transcriptional activation of host cell genes by one of these proteins has been proposed as a factor contributing to cellular transformation. The viruses share many features of infection and pathogenesis, although BLV causes B cell tumors whereas HTLV causes T cell tumors. It is important to understand how these viruses establish a latent but persistent infection in their hosts. The similarities between the viruses warrant a careful study of BLV infection because it can be experimentally manipulated in vivo. We have undertaken a detailed study of early infection by BLV in lambs, an experimentally susceptible host, to identify the tissues and host cells in which virus infection becomes established and to delineate the developing immune response. We will identify infected cells within tissues using single-cell methods to detect the virus in different stages of gene expression. Cells producing virus will be detected by immunocytochemical staining of viral proteins; cells in which viral RNA or DNA is present will be identified using in situ hybridization. The lineages of infected cells will be determined using histochemical assays and antibodies that are specific for cell lineage. We will monitor the humoral immune response during the establishment of BLV infection by measuring both antibodies against viral proteins and neutralizing antibodies that prevent viral infection. The presence in plasma of a factor that blocks expression of BLV in its host cells will be assessed. The onset of T cell-mediated cytolytic activity against autologous BLV-infected cells will be monitored. We will isolate monocytes from the blood and bone marrow of infected animals to determine whether cells of the macrophage lineage are infected by BLV and can produce infectious virus.